Grant: Proof of Principle Program - Phase I

Loss of epithelial barrier integrity is common to many oral and gastrointestinal diseases including ulcerative colitis, periodontitis, and diarrheal diseases. Putnins et al. have demonstrated that monoamine oxidase (MAO) B, a pro-oxidative enzyme, is increased in in vivo models of epithelial barrier disease. They showed that clinically approved MAO inhibitors (including deprenyl) dramatically improved the barrier, reduced periodontal disease, and protected the gastrointestinal tract barrier in a GI colitis model. These findings suggest that MAO inhibitors may be used to manage mucosal diseases. However, in their current form, MAO inhibitors cross the blood-brain barrier (BBB) and thus are associated with significant adverse effects and drug-drug interactions. In collaboration with Dr. Grierson, a medicinal/synthetic chemist, the team has designed novel, polar MAO B inhibitors that will not cross the BBB. To date, 37 novel molecules related to deprenyl have been synthesized and tested for activity and selectivity and two lead compounds have been identified. A provisional patent application was filed in August 2013. The goal of this project is to design and synthesize polar molecules that could selectively inhibit MAO B but not cross the BBB. With CIHR Proof of Principle (POP) Phase I funding, the team will synthesize and screen 100+ compounds and identify leads suitable for further in vivo studies. Drs. Putnins and Grierson have formed a collaborative partnership with the Centre for Drug Research & Development (CDRD), Canada's national drug development and commercialization centre. This partnership with CDRD has leveraged additional funding from CDRD's Innovation Fund to evaluate MAO B expression and to accelerate the preclinical development of lead compounds emanating from the work outlined in this POPI proposal. The goal at the end of year 1 is the development of three lead compounds that will be tested in vivo using existing funding and established animal models.